Bipolar disorder or manic-depressive illness is a major psychiatric illness that affects 1% of the world's population. It is characterized by alternation between the two extreme mood states of mania and depression. Psychosis can occur in either state and the lifetime suicide rate is 17%. Our 11 site consortium has been funded for over 15 years to collect DMA samples from patients with bipolar disorder and their families for genetic studies. We were recently selected by GAIN to be one of six diseases to be genotyped for whole genome association studies. GAIN will sponsor genotyping of 1158 Caucasian and 400 African American bipolar I cases. Controls will be shared with a corresponding project on schizophrenia (principal investigator: P. Gejman). These samples will be genotyped by the Broad Institute under contract from GAIN using the Affymetrix 500Kb chip. This will provide genotypes on approximately 500,000 SNPs and data on copy number variation genome-wide. The analyses will be conducted on a collaborative basis by 6 collaborating sites each of whom participated in the sample collection. UCSD will serve as the lead site and will be responsible for coordinating the analytic work between the participating sites. The case-control samples will be examined for population substructure and this information will be used as a covariate in the association analysis. Both single SNP and haplotype based methods will be employed for analysis of association. Gene-gene interactions will also be examined. Several possible genetically distinct subforms of illness will also be examined separately. Relevant genes and regions from the genome-wide association will be selected for replication in a second independent sample of 1,000 Caucasian cases and 1,000 controls, and 200 African-American cases and 200 controls. Replicated genes will be subjected to pathway analysis in an attempt to identify pathways involved in mechanisms of disease. Support is requested for the UCSD site in order to coordinate analytic effort between the sites, provide database, bioinformatic and statistical support for all the sites and to conduct the primary analysis of the data. [unreadable] [unreadable] [unreadable] [unreadable]